The Mutational Landscape of Metastatic Castration-Sensitive Prostate Cancer: The Spectrum Theory Revisited

[podsart]

Published in Advanced Prostate Cancer

Journal Scan / Research · February 09, 2021

The Mutational Landscape of Metastatic Castration-Sensitive Prostate Cancer: The Spectrum Theory Revisited

European Urology

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TAKE-HOME MESSAGE

This retrospective study of metastatic castration-sensitive (mCSPC) or biochemical-recurrent (BCR) prostate cancer aimed to evaluate the driver mutations across 269 samples (primary tumor 91%) based on volume of disease by conventional scans: 1) BCR; 2) oligometastatic – five or fewer metastatic sites; 3) poly-metastatic – more than five metastatic sites; and 4) de-novo mCSPC.

This study is interesting as the analysis of somatic genomic alterations (including TP53, WNT, and cell cycle) revealed a spectrum of metastatic biology supporting a redefinition of oligometastasis beyond the number of lesions. These findings require further validation of the tumor mutational profile to be used in the definition of metastatic prostate cancer, with potential therapeutic implications.

– Pedro C. Barata, MD

Abstract

This abstract is available on the publisher's site.

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BACKGROUND

Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical.

OBJECTIVE

To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.

DESIGN, SETTING, AND PARTICIPANTS

This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).

RESULTS AND LIMITATIONS

The frequency of driver mutations in TP53 (p =  0.01), WNT (p =  0.08), and cell cycle (p =  0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p =  0.002), and time to CRPC (95.6 vs 155.8 mo; p =  0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p =  0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p =  0.004) and DNA double-strand break repair (IRR 1.61; p <  0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p =  0.03) and the development of CRPC (HR 1.71; p =  0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined.

CONCLUSIONS

Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration.

PATIENT SUMMARY

Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.

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[LearnAll]

It makes a lot of sense to think of prostate cancer as a spectrum disorder just like so many other medical conditions. The proof is obvious...some men with metastasis live 10,20 or even 30 years and others pass away within 2 years of diagnosis.The number of mets and definitions are only for the sake of convenience and does not truly reflect the reality of heterogeniety of prostate cancer in different individuals.

A better classification would be to use androgen sensitivity ..which puts every man into one of the 3 categories (1) predominantly Androgen sensitive (2) Mixed type (3) Predominantly Androgen independent.( Incl. Aggressive Variants)

A patient can be classified in one of the 3 categories by the Nadir PSA achieved after 9 months of ADT. Lower the Nadir PSA ..higher the androgen sensitivity.

IMO, The treatment should be tailor made after thoroughly assessing the degree of aggressiveness. Current guidelines are assuming that every man's prostate cancer is aggressive and same assembly line treatments are recommended for everyone. This needs to give way to individualized treatment plan for each man.

Lastly, it is now accepted that continuous and strong suppression of androgen for long increases mutational burden.... at least the researchers who study intermittent ADT believe it.

[podsart in reply to LearnAll]

Makes sense

Guess eventually, will also , when available, also match genetics for person to specifically tailored treatments

[mrssnappy]

Interesting and thanks for sharing.

[Cooolone]

To be sure, and in agreement with replies previous to this, individualized and designed treatment modalities is and should be what becomes the new normal as medicine is finding more and more distinct profiling across patient diagnosis. Simply lumping all that fall into a broad range and group into a treatment modality and hoping for the above average response does a disservice to both the medical field and the patient. But maybe before, with the lack of accuracy that now exists in imaging and detection, this has changed, along with genetic profiling, tht this can happen at a level which allows comfortable prognosis using designed treatments more to the individual. Who knows, but to be sure, without the FDA getting on board and broadening the acceptable label use of testing and therapies, it won't happen anytime soon!

This has just been a recent lengthy conversation between myself and my MO, in regard to my diagnosis, which recently progressed to stage IV, mHSPC to the Peritoneal and Appendix with somatic mutations identified and low score MSI MMR genes identified. The fact that there is specific genetic mutation I possess, with drugs actually available that have shown great results to those mutations, BUT that I do not fit the neat little description of what type of patient it is labeled for precludes me from using the drug (as labeled)... Is problematic! Meaning I need to wait until progression occurs and the PCa becomes hormone resistant in order to have access. It's just something which is befuddling! My condition is so rare, there's just no ability to prognosticate the condition as recordings of patients with the PCa behaving or presenting itself as it has done in my body, just don't exist. So why then, and how does, my condition then fall into a treatment group definition, and it's limitations? Lol...

A long winded personal explanation of why I believe the standard molds and restrictions on care need to be broken! Hahaha

I do understand this may present a problem for tracking and understanding performance of given treatments, but the needs of the many, or the pharmaceuticals should not outweigh the need of the patient or few! Patient diagnosis and care should outweigh regulatory control over medicine application! Just a personal opinion based upon my experience take it for what it's worth

Best Regards

[podsart in reply to Cooolone]

Good points, much luck

[MateoBeach]

That study and much much more current PCa research is now being presented at the ASCO GU 2021 virtual conference this week. Anyone can log on for the free portions including the poster (brief) presentations of most of the work. It is a rich feast!

Just search ASCO GU 2021 and follow the links.

[podsart]

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